ABSTRACT The increased aromatase activity in the abundant fat tissues of obese men results in enhanced conversion of androgens to estrogens, (estradiol [E2], estrone), leading to high estrogen levels. This in turn sends negative feedback to the hypothalamic-pituitary-gonadal unit resulting in reduced gonadotropins, and decreased testosterone (T) production and a condition called hypogonadotropic hypogonadism (HHG). Accordingly, T therapy may only lead to increased substrate (T) for aromatase activity and further E2 increase. Although weight loss (WL) results in increased T levels, WL by lifestyle change alone is limited by the lower magnitude of rise in T and weight regain which is common. Aromatase inhibitors (AIs) can reduce E2 production and increase T but little or no information is available on the efficacy of adding an AI to WL to produce enhanced aromatase inhibition in improving symptoms in obese men with HHG. The primary objective of this proposal is to evaluate the efficacy of an AI as an adjunct to WL (AI+WL) compared to WL alone in severely obese men with HHG. The central hypothesis of this proposal is that the addition of an AI to WL (diet+exercise) will lead to reversal of the hormonal abnormality in obesity-associated HHG resulting in improvement in hypogonadal symptoms without significant adverse effects on body composition (and metabolic risk factors) and bone. We hypothesize that: 1) AI+ WL will completely reverse the hormonal abnormality in obesity-associated HHG because of the additional effect of an AI over and above that of WL alone in reducing aromatase activity in the expanded adipose tissue volume, 2) AI+ WL will result in greater improvement in muscle strength, muscle mass and symptoms compared to WL alone because of the greater increase in T, 3) AI+WL will lead to a greater increase in lean mass due to a greater increase in T compared to WL alone but may attenuate the loss of fat mass and metabolic improvement from WL due to a greater reduction in E2, and 4) although AI+WL will have the potential of reducing bone mineral density (BMD) and impairing bone quality because of a greater reduction in E2 compared to preservation by WL alone, this will be minimized because of high levels of E2 at baseline and the increased muscle mass. We will randomize 100 obese men with BMI ?35 kg/m2, total T <300 ng/dl, E2 > 40 pmol/L and luteinizing hormone <9 mIU/L to AI, anastrozole (1 mg daily), +WL, or placebo daily+WL for 12 months. Additionally as a secondary aim, we will elucidate the mechanism for our central hypothesis in an integrated manner by using simple/partial correlation and multiple regression analyses to determine which of the hormonal factors and mediators may explain the observed changes in muscle strength and symptoms, muscle mass, body composition (and metabolic risk factors), BMD and bone quality. Results from this study will establish the utility and safety of AIs in conjunction with WL in men with severe obesity among whom the etiology of hypogonadism is related to excess estrogen production, thus representing a potential strategy among the growing number of obese hypogonadal men.